PROJECT SUMMARY/ABSTRACT There is an epidemic of chronic kidney disease of unknown etiology in Central America (referred to as Mesoamerican nephropathy, or MeN) affecting primarily young males employed in manual labor. The MeN epidemic is not explained by traditional risk factors for kidney disease, such as hypertension or diabetes. A leading hypothesis for the etiology of this disease is that occupational heat exposure compounded by genetic susceptibility leads to chronic volume depletion, causing repeated acute kidney injuries that eventually lead to chronic kidney disease. Research into this hypothesis is limited and no studies to date have examined gene-environment interactions. Using the extensive exposure and outcome data collected from the 569 participants of the MesoAmerican Nephropathy Occupational Study (MANOS), this epidemiologic study aims to investigate the effects of occupational heat exposure on acute kidney injury and chronic kidney disease in a population with multiple nephrotoxicant co-exposures (e.g. medications, heavy metals, and agrichemicals). The proposed study will also examine gene-environment interactions in MeN, using genetic variants that were associated with MeN in independent analyses. With a team of sponsors and mentors whose expertise includes environmental epidemiology, nephrology, exposure science, and genetics, Zoe Petropoulos (PI) will undertake the following specific aims: 1) investigate the effects of total heat load on acute kidney injury and declines in kidney function through intermediate outcomes of volume depletion and muscle damage, and 2) examine whether genetic variants modify the associations between total heat load, intermediate outcomes, and kidney injury and function. This research will inform the understanding of the etiology of MeN and individual susceptibility to the disease, which will help to identify effective intervention strategies. More broadly, this research will address an understudied disease epidemic and investigate a non-traditional mechanism of kidney disease, while simultaneously examining the health effects of extreme heat exposure in the context of multiple co-exposures.